Some personal views on nanotechnology, science and science policy from Richard Jones

Ken Donaldson on nanoparticle toxicology

I’ve been running in and out of a three day course on nanotechnology intended for chemists working in the chemistry industry (Nanotechnology for Chemists), organised by me and my colleagues at Sheffield on behalf of the Royal Society of Chemistry. Yesterday I swapped from being a lecturer to being a pupil, to hear a lecture about nanoparticle toxicity, given by Ken Donaldson of the University of Edinburgh, the UK’s leading toxicologist specialising in the effects of environmental nanoparticles. This is a brief summary of his lecture as I understood it (all misunderstandings and misapprehensions are my fault, of course).

His lecture began with the disclaimer that most nanotechnology won’t pose a health risk at all; what’s at issue is the single class of free (i.e. not incorporated in a matrix, as happens in a nanocomposite material), manufactured, insoluble nanoparticles. Of the potential portals of entry – the lungs, the gut and the skin – he felt that the main danger was the lungs, so the main potential danger, both for industrial workers and users, was nanoparticles in the air.

It’s been known for a long time that particles cause lung disease; he gave a number of examples (illustrated by gruesome photographs), including coal miner’s lung, cancer and silicosis from quartz particles and asbestos. The latter causes a number of diseases, including mesothelioma, a particularly nasty cancer seen only in people exposed to asbestos, characterised by long latency period and with a uniformly fatal final outcome. So it’s clear that particles do accumulate in the lungs.

In terms of what we know about the effect of nanoparticle exposures, there are four distinct domains. What we know most about are the nanoparticles derived from combustion. We also know a fair amount about bulk manufactured particles, like titanium dioxide, which have been around a long time and which typically contain significant fractions of nanosized particles. Of course, the effects of nanoparticles used in medical contexts have been well studied. The final area is the least studied – the effect of engineered free nanoparticles.

So what can we learn from environmental nanoparticles? The origin of these particles is overwhelmingly from combustion; in the UK only 13% of exposure comes from non-combustion sources, usually the processes of natural atmospheric chemistry. The most important class of nanoparticles by far are those deriving from traffic exhaust, which account for 60% of exposure. These particles have a basic size of tens of nanometers, though they clump with time into micron sized aggregates, which are very easily respirable.

These particles have no problem getting deep within the lungs. Of the 40 nm particles, perhaps 30% can get to the very delicate tissues in the periphery of the lung, where they deposit very efficiently (smaller particles actually are less effective at getting to the lung as they tend to be taken up in the nose). The structures they interact with deep in the lung – the bronchal epithelial cells – are very small and fragile, and the distances separating airways from the blood are very small. Here the particles cause inflammation, which is essentially a defense reaction. We’re familiar with inflammation of the skin, marked by swelling – fluid bathes the region and white blood cells engulf damaged tissue and microbes, leading to pain, heat, redness and loss of function. Of course in the lung one can’t see the inflammation, and there are no pain receptors, so inflammation can be less obvious, though the swelling can easily cut off air flow leading to very disabling and threatening conditions.

It’s believed that there is a generic mechanism for lung inflammation by combustion-derived nanoparticles, despite the wide variety of different kinds of chemistry in these particles. All these have in common the production of free radicals, which leads to oxidative stress, which in turn leads to inflammation. DIfferent types of nanoparticles cause oxidative stress through different mechanisms. Metal nanoparticles – as found in welding fumes – yield one mechanism, surface born organics (as are found in soot), have another, and materials like carbon black, titanium dioxide and polystyrene latex, which are not very intrinsically toxic, operate through some generic surface mechanism. Clearly it is the surface area that is important, so nanoparticles cause more inflammation than the same mass of fine respirable particles, in the 2-3 micron range, composed of the same materials. In passing one can note that diesel fumes are particularly harmful, dealing a triple blow through their combination of surfaces, metals and organics. These pathways to oxidative stress are very well understood now, so this is a well-found paradigm.

Inflammation due to the oxidative stress caused by nanoparticles from pollution then leads to a number of different diseases, including cardiovascular diease, asthma, scarring, cancer and chronic obstructive pulmonary disease). Their involvement in cardiovascular disease is perhaps unexpected, and to understand it we need to understand where the nanoparticles go. We have some rather hypothetical toxicokinetics based on a few experiments using radioactive, insoluble tracer particles. Having entered the nose or lung, a few studies suggest that they can go directly to the brain. The route from the lung to the blood is well understood, and once in the blood there are many possible ultimate destinations. It’s doubtful that nanoparticles could enter the blood directly from the gut or skin. A mechanism for the involvement of nanoparticles in cardiovascular disease is suggested by studies in which healthy Swedish student volunteers rode a bike in an atmosphere of diesel fumes (at levels comparable to highly polluted city streets). This leads to measurable vascular dysfunction throughout the whole body, and a reduction in the ability to dissolve blood clots (similar effects will be observed in smokers, who self-administer nanoparticles). This suggests that pollution nanoparticles could cause cardiovascular disease either through lung inflammation or through the direct effect of bloodborn particles, leading to the worsening of coronary artery disease or increased blood clotting.

A study using radioactive carbon has suggested that nanoparticles can enter the brain directly from the nose, via the olfactory bulb – this is the route into the central nervous system used by the polio virus, and it doesn’t required crossing the blood-brain barrier. Studies of brain tissue in people living in highly polluted cities like Mexico City have shown pathological changes simiilar to those seen in victims of Parkinson’s and Alzheimer’s occurring as a result of the effect of pollution-derived nanoparticles.

The potential comparison between carbon nanotubes and asbestos is worth considering. Very large exposures to asbestos in the past have caused many cases of fatal lung disease. The characteristics of asbestos which cause this disease – and these characteristics are physical, not chemical – are that they are thin, persistent in the body, and long. Carbon nanotubes certainly match the first two requirements, but it is not obvious that they fulfill the third. Asbestos fibres need to be 20 microns long to demonstrate toxic effects; if they are milled to shorter lengths the toxicity goes away. Carbon nanotubes of this length tend to curl up and clump. On the other hand rat experiments on the effect of nanotubes on the lungs show distinctive fibrosing lesions. Donaldson has just written an extensive review article about nanotube toxicity which will be published soon.

From the regulatory point of view there are some difficulties as regulations usually specify exposure limits in terms of mass concentration, while clearly it is surface area that is important. In the USA NIOSH thinking of reducing limits by a factor of 5 for ultrafine TiO2. Fibres, though, are regulated by number density. The difficulties for carbon nanotubes are that they are probably too small to see by standard microscopy, and they curl up, so although they should be classifed as fibres by WHO definitions probably aren’t going to be detected. In terms of workplace protection local exhaust ventilation is much the best, with almost all masks being fairly useless. This applies, for example, to the masks used by some cyclists in polluted cities. They can, however, take comfort from the fact that their exposure to nanoparticles is significantly smaller than the exposure of the people inside the vehicles who are causing the pollution.

My conclusion, then, is if you are worried about inhaling free nanoparticles (and you should be) you should stop travelling by car.

4 thoughts on “Ken Donaldson on nanoparticle toxicology”

There is a saying in toxicology going back to the ancient greeks that “the dose makes the poison”, in other words, that just about everything is harmless in small doses and fatal in large doses. I suppose the same is true of nanoparticles. In the natural world there would always be a certain exposure to nanoparticles, organic and inorganic. Organisms would evolve the ability to tolerate a certain dosage. But in our modern world, various processes may greatly increase environmental quantities of nanoparticles, and this is where the problem arises.

As far as engineered nanoparticles, presumably we would also see a dose dependent relation. If there are just a few of them around then it’s probably OK. But if we somehow fill the environment with clouds of these particles, we are more likely to see serious toxicological reactions.

I’m reminded of Neal Stephenson’s novel The Diamond Age, where the air was full of nanoparticles, casualties of a sort of low-level, ongoing war between good guy and bad guy nanobots. People had to wear face masks when they went outdoors (presumably, enhanced face masks using nanotech for good filtering). Beyond this kind of fictional scenario it’s kind of hard to see what would fill the air with engineered nanoparticles.

Another point to make about free, airborne nanoparticles is that they don’t last very long (the driving force for aggregation of particles with such high surface to volume ratios is very high). A striking comment that Donaldson made was that, although concentrations of nanoparticles are pretty high close to a road, you only needed to go about 50 m away from the road for the concentrations to drastically fall.

I seem to remember reading shortly after the discovery of fullerenes, that humans have been making fullerenes by burning fires for thousands of years.
It was suggested or proven (I can’t remember which), that since humans have been doing this for so long that we have evolved an unusually high tolerance to such exposure (at least for some nanoparticles) compared to other animals. This may mean that animal models might give us an overly pessimistic assessment of toxicity in humans.

It’s certainly true that nanoparticles from combustion are very abundant in wood-smoke. This doesn’t mean they’re harmless, though, but it does undermine the argument that nanoparticles are especially dangerous because we have no history of prior exposure to them. But then, there are plenty of things that we have a long history of coexisting with that are pretty harmful.